title: Selective inhibition of bacterial and human topoisomerases byN-arylacylO-sulfonated aminoglycoside derivatives.
abstract: Numerous therapeutic applications have been proposed for molecules that bind heparin-binding proteins. Development of such compounds has primarily focused on optimizing the degree and orientation of anionic groups on a scaffold, but utility of these polyanions has been diminished by their typically large size and non-specific interactions with many proteins. In this studyN-arylacylO-sulfonated aminoglycosides were synthesized and evaluated for their ability to selectively inhibit structurally similar bacterial and human topoisomerases. It is demonstrated that the structure of the aminoglycoside and of theN-arylacyl moiety imparts selective inhibition of different topoisomerases and alters mechanism. The results here outline a strategy that will be applicable to identifying small, structurally defined oligosaccharides that bind heparin-binding proteins with a high degree of selectivity.
authors.affiliation: Division of Medicinal and Natural Products Chemistry, Department of Pharmaceutical Sciences and Experimental Therapeutics, University of Iowa, Iowa City, IA 52242, USA.
authors.forename: Amanda M
authors.initials: AM
authors.lastname: Fenner
authors.forename: Lisa M
authors.initials: LM
authors.lastname: Oppegard
authors.forename: Hiroshi
authors.initials: H
authors.lastname: Hiasa
authors.forename: Robert J
authors.initials: RJ
authors.lastname: Kerns
keywords: aminoglycoside derivatives; ciprofloxacin-induced DNA cleavage; glycosaminoglycan mimic; sulfated oligosaccharide; topoisomerase inhibitor